Neuroprotection by Allopregnanolone through Modulation of GABAA Receptors

描述（由申请人提供）：全脑缺血，如中风或心脏骤停期间发生的，仍然是美国的主要杀手，急性发作后存活的患者会出现许多神经功能缺损。目前，还没有治疗方法来预防心脏骤停或中风造成的神经损伤。开发有效治疗方法的主要障碍之一是缺乏对神经元在缺氧时如何以及为什么死亡的理解。兴奋性毒性，即CMS中谷氨酸的过度释放，是在缺血期间发生的病理生理事件，并且被认为是细胞死亡的主要罪魁祸首。然而，使用谷氨酸受体拮抗剂阻断兴奋性毒性的疗法在人类中导致许多有害的副作用。或者，增加抑制性音调的水平可以防止兴奋性毒性。使用GABA受体激动剂阻断兴奋性毒性的研究产生了不一致的结果，导致对GABA活化化合物作为治疗剂的兴趣丧失。最近的研究揭示了这些发现的可能解释，这些研究表明，GABAA受体蛋白在缺血后减少，可能降低了GABA增强药物的有效性。我们的实验室已经能够在培养的浦肯野细胞中证实这些发现，浦肯野细胞接受强大的兴奋和抑制驱动，特别容易受到缺血的影响。使用电生理记录来评估GABAA受体的功能活性，再加上分子生物学和组织学技术，我计划表征缺血后GABAA受体活性的功能下降，并确定神经甾体别孕烯醇酮授予的神经保护机制。

DESCRIPTION (provided by applicant): Global cerebral ischemia, as experienced during stroke or cardiac arrest, continues to be a major killer in the US and those who survive the acute attack experience many neurological deficits. Currently, there are no therapies to prevent neurological damage from cardiac arrest or stroke. One of the major obstacles for developing effective treatments is the lack of understanding how and why neurons die when deprived of oxygen. Excitotoxicity, excessive release of glutamate in the CMS, is a pathophysiological event that occurs during ischemia and is thought to be a major culprit in cell death. However, therapies using glutamate receptor antagonists to block excitotoxicity result in many detrimental side effects in humans. Alternatively, increasing the level of inhibitory tone may prevent excitotoxicity. Studies using GABA receptor agonists to block excitotoxicity have yielded inconsistent results, resulting in a loss of interest in GABA activating compounds as therapeutic agents. A possible explanation for these findings was unveiled in more recent studies which show that GABAA receptor protein is decreased following ischemia, possibly decreasing the effectiveness of GABA potentiating drugs. Our lab has been able to reaffirm these findings in Purkinje cells in culture, which receive robust excitatory and inhibitory drive and are particularly susceptible to ischemia. Using electrophysiological recordings to asses the functional activity of GABAA receptors, coupled with molecular biology and histology techniques, I plan to characterize the functional decline in GABAA receptor activity following ischemia and determine the mechanism of neuroprotection granted by the neurosteroid allopregnanolone.